Enhancing Efficacy of Vaccines Administered Via the Respiratory Tract

ABSTRACT

Disclosed herein are vaccine compositions comprising live attenuated virus with anti-antibody to improve efficacy. Specifically exemplified herein is a composition comprising live attenuated cold adapted influenza virus and an enhancing amount of IgG anti-IgA antibody to temporarily inactivate IgA defenses. Also disclosed herein are methods of immunizing a subject to protect against influenza comprising administering compositions taught herein.

BACKGROUND

Influenza, commonly known as the flu, is an infectious disease of birdsand mammals caused by an RNA virus of the family Orthomyxoviridae (theinfluenza viruses). In humans, common symptoms of influenza infectionare fever, sore throat, muscle pains, severe headache, coughing,weakness, and fatigue. (Merck Manual Home Edition. Influenza: ViralInfections). In more serious cases, influenza causes pneumonia, whichcan be fatal, particularly in young children and the elderly. Sometimesconfused with the common cold, influenza is a much more severe diseaseand is caused by a different type of virus. Eccles, R (2005).“Understanding the symptoms of the common cold and influenza”. LancetInfect Dis 5 (11): 718-25. Although nausea and vomiting can be produced,especially in children, (Merck Manual Home Edition. Influenza: ViralInfections) these symptoms are more characteristic of the unrelatedgastroenteritis, which is sometimes called “stomach flu” or “24-hourflu”. Seasonal Flu vs. Stomach Flu by Kristina Duda, R.N.; accessed Mar.12, 2007 (Website: “About, Inc., A part of The New York Times Company”).

Flu spreads around the world in seasonal epidemics, killing millions ofpeople in pandemic years and hundreds of thousands in non-pandemicyears. Three influenza pandemics occurred in the 20th century and killedtens of millions of people, with each of these pandemics being caused bythe appearance of a new strain of the virus in humans. Often, these newstrains result from the spread of an existing flu virus to humans fromother animal species. Since it first killed humans in Asia in the 1990s,a deadly avian strain of H5N1 has posed the greatest risk for a newinfluenza pandemic.

Vaccinations against influenza are most commonly given to high-riskhumans in industrialized countries (WHO position paper: influenzavaccines WHO weekly Epidemiological Record 19 Aug. 2005, vol. 80, 33,pp. 277-288), and to farmed poultry (Villegas, P (1998). “Viral diseasesof the respiratory system”. Poult Sci 77 (8): 1143-5. PMID 9706079). Themost common human vaccine is the trivalent flu vaccine that containspurified and inactivated material from three viral strains. Typicallythis vaccine includes antigenic material from two influenza A virussubtypes and one influenza B virus strain and is given by intramuscularinjection. A vaccine formulated for one year may be ineffective in thefollowing year; the influenza virus changes rapidly over time and henceannually different strains become dominant.

Another vaccine, live attenuated, cold-adapted influenza vaccine(LACAIV) is becoming widely recognized as a better alternative toconventional vaccines, especially in children ages 1-5 years old. Oneclear advantage is that this vaccine can be administered via a nasalspray into the upper respiratory tract as opposed to intramuscularinjection. Further, LACAIV has theoretical advantages over intramuscularinfluenza shots in that it induces sIgA antibody which prevents fluinfection of the upper respiratory tract (Renegar, Kathryn B. and Small,Parker A., Jr., Immunoglobulin A mediation of murine nasalanti-influenza virus immunity. J. of Virology, 65:2146-2148, 1991), cellmediated immunity which enhances recovery (Bender, B. S. Coroghan, T.,Liping, Z and Small, P. A. Jr., Transgenic mice lacking majorhistocompatibility complex-restricted class 1 T-cells have delayed viralclearance and increased mortality following influenza virus challenge,J. Exp. Med. 175:1143-1145, 1992), and serum IgG antibody which has longbeen known to prevent infection of the lungs (viral pneumonia) (Loosli,C. G., D Hamre, and B. D. Berlin, Airborne influenza virus A infectionin immunized animals, Trans. Ass. Amer. Physicians 66:222-230,1953), butnot to prevent infection of the upper respiratory tract (Ramphal, R.Cogliano, R. C. Shands, J. W., Jr. and Small, P. A., Jr., Serum antibodyprevents murine influenza pneumonia but not influenza tracheitis,Infect. Immun. 25:992997, 1979). These theoretical advantages of LACAIV,however, are not always observed in field trials. In fact, it has beenshown that in individuals age 18 to 46 years old, LACAIV issignificantly less effective than intramuscular injection of aninactivated vaccine. (Ohmit et al., Prevention of Antigenically DriftedInfluenza by Inactivated and Live Attenuated Vaccines, N Eng J Med,355:2513-2522, 2006). This problem is perplexing and casts a shadow overthe use of LACAIV as a viable vaccine alternative for adults.

SUMMARY

According to one embodiment, the subject invention provides a solutionto the reduced efficacy of LACAIV in older children and adults which canalso be applied to other vaccines administered to the upper respiratorytract. The inventors have observed that LACAIV is likely neutralized inadults by the action of secretory IgA antibody in the nasal passages.Because of this neutralization, viral growth of the attenuated vaccineis limited, and the necessary immunogenic dose of virus is not achieved.Furthermore, the inventors have developed an improvement to the LACAIVto overcome this problem. Accordingly, in one embodiment, the inventionis directed to a vaccine administered via the respiratory tract, such asLACAIV, which further comprises an effective amount of anti-IgA antibody(anti-antibody). The addition of anti-antibody serves to neutralize orinactivate the activity of sIgA antibody to the influenza virus, whichwill allow a sufficient amount of the vaccine virus to replicate so asto be able to induce an acceptable level of immunity.

As will be further noted below, anti-antibody can be added to vaccinesdirected to other viruses and microorganisms which are configured foradministration in the upper respiratory tract such as viral vectoredgene therapy. Furthermore, the LACAIV is designed as a vaccine againstseasonal influenza (i.e. H3N2, H1N1 & B). An additional advantage of theLACAIV/anti-antibody embodiment is that it may protect against otherinfluenza types, such as pandemic influenza (e.g. H5N1). This is becausethe sIgA antibody induced by LACAIV can be cross-reactive (Waldman, R.H., F. M. Wigley and P. A. Small, Jr. Specificity of RespiratorySecretion Antibody against Influenza Virus, J. Immun,106:1477-1483,1970), whereas serum IgG antibody is specific.

DETAILED DESCRIPTION

Flu-mist is a LACAIV product manufactured and marketed by MedImmuneVaccines, Inc. Gaithersburg, Md. 20878. One embodiment of the subjectinvention relates to a Flu-mist product further comprising an enhancingamount of anti-antibody. An enhancing amount of anti-antibody in avaccine referred to herein relates to an amount which serves to increasethe efficacy of the vaccine. Increased efficacy relates to a lessernumber of flu cases or symptoms, or both, in vaccine/anti-antibodyversus vaccine alone; increased serum antibody titer against targetpathogen in vaccine/anti-antibody versus vaccine alone; or a combinationof the foregoing. The Ohmit et al. reference referred to above providesbackground on this issue.

In other embodiments, the subject invention pertains to a viral vaccinedesigned for intranasal delivery which comprises anti-antibody. Forexample, viral vaccines against other diseases including but not limitedto the common cold, RSV, SARS, and virus vectored (e.g., AAV or adenovectored) cystic fibrosis therapy can be combined with anti-antibody totemporarily inactivate IgA immunity in the upper respiratory passages.The anti-antibody may be of any immunoglobulin class (IgG, IgA, IgM,IgD, IgE) or a synthetic molecule, and may be produced in murine,equine, porcine, bovine, canine, feline, ovine or other species. It alsocould be produced as a monoclonal antibody (e.g. murine antibody), orhumanized version of an antibody. In a specific embodiment, theanti-antibody is IgG anti-human IgA.

Another embodiment of the invention pertains to a method of immunizing asubject against a target pathogen. The method comprises administeringintranasally a therapeutically effective amount of a compositioncomprising a vaccine and anti-antibody to the subject. A therapeuticallyeffective amount comprises that amount to induce an immune response inthe recipient. Preferably, the therapeutically effective amount is anamount to provide protective immunity against the target pathogen. Thevaccine may be tailored to immunize against viruses, bacteria,mycobacteria, fungi and protozoa in which immunization is neutralized bysIgA in the upper respiratory passages.

In one embodiment, the vaccine may comprise live attenuated virus,inactive virus, or viral antigens (e.g., viral polypeptides ornucleotides), or a combination thereof. In a specific embodiment, thecomposition comprises LACAIV and anti-antibody. In a more specificembodiment, the composition comprises an enhancing amount ofanti-antibody.

The anti-antibody may be obtained from a number of suitable sources.Examples of sources include, but are not limited to, blood fromimmunized animals, colostrum from immunized animals, peptide synthesis,recombinant production and the like. In a specific embodiment, thesource is bovine colostrom of animals immunized with human IgA. Usingbovine colostrom as a source has an advantage in that every human whoconsumed cow's milk in their youth and perhaps adulthood has undoubtedlyhad their upper respiratory passages exposed to bovine IgG antibody.Thus, bovine colostrom provides an exceptionally safe source of product,as undesired side effects will be minimal.

In another embodiment, the subject invention pertains to an article ofmanufacturer comprising vaccine and anti-antibody. The article ofmanufacture can be a vial, a syringe, a vaporizer or a nasal sprayapplicator. In an alternative embodiment, the subject invention pertainsto a kit comprising a nasal spray applicator comprising vaccine and anasal spray applicator comprising IgG anti-IgA antibody.

Those skilled in the art will appreciate that other components may beadded to composition embodiments suitable for the mode ofadministration. For example, vaccines often include adjuvant,pharmaceutically acceptable carriers, water, etc. For example, U.S. Pat.Nos. 7,112,332; 6,780,421; 6,613,321; 6,740,325; and 6,562,352 teachvarious components that may be added to vaccines.

The disclosures of the cited patent documents, publications andreferences are incorporated herein in their entirety to the extent notinconsistent with the teachings herein. It should be understood that theexamples and embodiments described herein are for illustrative purposesonly and that various modifications or changes in light thereof will besuggested to persons skilled in the art and are to be included withinthe spirit and purview of this application.

1. A composition comprising live attenuated cold adapted influenza virusand anti-antibody.
 2. A composition comprising a vaccine andanti-antibody.
 3. The composition of claim 2, wherein said vaccinecomprises live attenuated virus, inactive virus, or viral antigens. 4.The composition of claim 2, wherein said anti-antibody is IgG anti-IgAantibody.
 5. The composition of claim 2 wherein said anti-antibody isIgM anti-IgA antibody.
 6. An article of manufacture comprising a vaccineand anti-antibody.
 7. A method of vaccinating a subject to protectagainst influenza, said method comprising administering to said subjecta therapeutically effective amount of a composition comprising liveattenuated cold adapted influenza virus and anti-antibody.
 8. The methodof claim 7, wherein said composition is administered intranasally.
 9. Ina method of vaccinating a subject to protect against a target pathogencomprising administering to said subject a vaccine intranasally, theimprovement comprising co-administering anti-IgA with said vaccine. 10.A method of vaccinating a subject to protect against a target pathogen,said method comprising administering to said subject a therapeuticallyeffective amount of a composition comprising vaccine and anti-antibody.